While several previous studies have suggested a role for biomarker profiling in the management of transplant patients, two important questions have surfaced regarding the reality of their potential use in clinical practice. First, can these biomarkers inform individual patient management and optimize the ability to personalize immunosuppression (IS) regimens? Second, can therapeutic decisions informed by gene expression profiling improve both short- and long-term clinical outcomes? We believe that these questions appropriately frame the next frontier in biomarker research and we therefore propose a (U01) multi-center, interventional, randomized controlled clinical trial that translates findings from our previous work. We will integrate molecular diagnostics into clinical practice, and demonstrate their value in the management of patients following kidney transplantation (KT). Our central hypothesis is that gene expression profiling can generate actionable information for individual patients that can help inform IS decisions on regimen efficacy and safety, provide mechanistic insights into, and predict graft outcomes. Therefore, we will test: 1) the effectiveness and safety of integrating actionable real-time molecular information from serial blood gene expression profiling ('serial biomarker monitoring' - SBM) to help inform the management of IS therapy following KT. We will compare SBM to the current standard of care (SOC), comparing graft outcomes between the two groups. If successful, we will show that actionable information derived from SBM of individual patients will allow clinicians to better manage IS following KT and demonstrate that this strategy is effective and safe, likely re-defining clinical practice and allowing for a personalized approach to post-KT management. We will also test: 2) the value of integrating peripheral blood and biopsy gene expression profiling t predict graft outcome, and to better understand the mechanistic basis of acute and chronic rejection. The study design allows for the study of serial profiling of blood and profiling of a 24 month exist biopsy for both the SBM and SOC cohorts. Therefore, we will first establish the value of the molecular phenotype and challenge the current histology 'gold standard'. We will also correlate serial gene expression profiles in the blood (including a suite of next generation molecular assays of immune activation and epigenetic regulation to purified subsets of blood cells) to clinical outcomes and to the 24 month biopsies, including both standard histology and molecular phenotypes. If successful, we will show that molecular profiling of the biopsy can provide a phenotype and assessment of graft status equivalent to the combination of clinical, laboratory and histology assessments, and better predict graft outcome. We will also show that SBM, including new assays of epigenetic regulation can predict molecular signals in subsequent biopsies, providing novel insights into the molecular basis of IS efficacy. The goal of this clinicl trial planning (R34) grant is to finalize all aspects of the clinical trial, and its associated mechanistic studies so that if funded, the U01 can proceed expediently and without delay.